PNU-140690 represented by the following formula (I) is known to be useful as an anti-HIV agent being developed in recent years. As a useful synthetic intermediate for PNU-140690, 3-hydroxy-3-(2-phenylethyl)hexanoic acid represented by the following formula (II) is known. This 3-hydroxy-3-(2-phenylethyl)hexanoic acid has one asymmetric carbon atom and includes an (R) isomer and an (S) isomer, and only a racemate (racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid) is synthesized according to a conventional method. Of these, an (R) isomer of the following formula (III) [(R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid] is preferably used as the above-mentioned synthetic intermediate.
As a method of optical resolution of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid from the above-mentioned racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, a method using (−)-norephedrine [(1S,2S)-norephedrine] has been conventionally reported (J. Org. Chem., Vol. 63, No. 21, 1998, 7348-7356). According to this method, however, (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid having an optical purity of not less than 98% e.e. is obtained after two times of recrystallization of a salt with (−)-norephedrine (92% e.e.), which is industrially inefficient. In addition, a method such as this has a problem that the yield of a highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid throughout the reaction system, in other words, the total yield of highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid relative to racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid (hereinafter sometimes to be simply referred to as “total yield”) is low (about 27%). In the above-mentioned report, it is described that even the use of generally used amine, such as phenylglycinol, ephedrine, sparteine and α-methylbenzylamine, did not lead to an effective optical resolution, and there is a demand on a method capable of efficiently affording highly optically pure (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid in a higher total yield.
In the meantime, as an intermediate for the above-mentioned 3-hydroxy-3-(2-phenylethyl)hexanoic acid, racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate of the following formula (IV) is known.
As a method for producing such racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate, a method comprising addition of a lithium salt of ethyl acetate to 1-phenyl-3-hexanone in tetrahydrofuran (THF) is known. For preparation of a lithium salt of ethyl acetate, however, deprotonation from ethyl acetate with a strong base such as lithium dialkylamide and the like is necessary, which is generally conducted by a reaction at an ultra-low temperature at around −78° C. (WO99/12919, Kristina S Fors et al, J. Org. Chem. 1998, 63, 7348-7356). A reaction at such an ultra-low temperature contains many industrially disadvantageous aspects, for example, it requires a special cooling unit and the operation is complicated and the like.
As a method for producing racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate in a temperature range that does not require a special cooling unit, the use of Reformatskii reaction is considered. The Reformatskii reaction is a conventionally known reaction which produces β-hydroxyacid ester by condensation of α-halogen ester and a carbonyl compound such as aldehyde, ketone and the like in the presence of zinc. For this Reformatskii reaction to proceed smoothly, the above-mentioned zinc needs to have a high activity (reactivity). As a method for producing activated zinc, the following conventional methods (1)-(5) are known. Any activated zinc obtained by these methods has a problem as shown in the following. The method is not practical for use for the above-mentioned Reformatskii reaction and racemic ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate could not be obtained in a sufficient yield.    (1) A method for preparing metallic zinc by reducing zinc salt such as zinc chloride and the like with potassium, magnesium, lithium and the like.
This method has a problem in safety because a water-prohibiting metal is used and the like.    (2) A method for activating metallic zinc with hydrochloric acid.
According to this method, application to a Reformatskii reaction, which is a water-prohibiting reaction, requires activation of zinc, complete removal of the acid and drying, and the preparation is complicated and impractical.    (3) A method for activating zinc by treating metallic zinc with a copper salt or silver salt in acetic acid to give an alloy with copper or silver.
Because alloy is prepared in acetic acid, acetic acid needs to be completely removed by washing with water, and only after drying on washing with water, can it be used for a Reformatskii reaction, which is a water-prohibiting reaction, and the preparation is complicated and impractical.    (4) A method for activating zinc by ultrasonic wave.
In this method, every facility used for the production of activated zinc requires a sufficiently strong ultrasonic oscillator. Therefore, this method is not entirely practical.    (5) A method for activating zinc by stirring zinc with chlorotrimethylsilane in ether.
This method is defective in that a highly inflammable solvent such as ether is used and the activity of the obtained zinc is not always high enough.
In the reaction using the above-mentioned activated zinc, a waste containing zinc is produced and a special waste treatment is necessary to avoid environmental pollution.
In the above-mentioned reaction, a bromoacetic acid ester is used. Bromoacetic acid ester is expensive and shows strong tearing property, and the reaction using the same has safety and health problems.
The present invention has been made to solve the above-mentioned problems and aims at providing a production method capable of efficient production of (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid useful as a starting material of a pharmaceutical agent from racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid, with a high optical purity and in a relatively high total yield.
In addition, another object of the present invention is to provide a method of producing 3-hydroxy-3-(2-phenylethyl)hexanoic acid ester safely and at a lower cost than a conventional method, by the use of general production apparatuses.
As a result of intensive studies in an attempt to solve the above-mentioned problems, the present inventors have completed the present invention. The present invention provides the following.